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Gerry Melino - One of the best experts on this subject based on the ideXlab platform.

  • myoblasts rely on tap63 to control basal mitochondria respiration
    Aging (Albany NY), 2018
    Co-Authors: Veronica Ciuffoli, Gerry Melino, Anna Maria Lena, Alessandra Gambacurta, Eleonora Candi
    Abstract:

    p53, with its family members p63 and P73, have been shown to promote myoblast differentiation by regulation of the function of the retinoblastoma protein and by direct activation of p21Cip/Waf1 and p57Kip2, promoting cell cycle exit. In previous studies, we have demonstrated that the TAp63γ isoform is the only member of the p53 family that accumulates during in vitro myoblasts differentiation, and that its silencing led to delay in myotube fusion. To better dissect the role of TAp63γ in myoblast physiology, we have generated both sh-p63 and Tet-On inducible TAp63γ clones. Gene array analysis of sh-p63 C2C7 clones showed a significant modulation of genes involved in proliferation and cellular metabolism. Indeed, we found that sh-p63 C2C7 myoblasts present a higher proliferation rate and that, conversely, TAp63γ ectopic expression decreases myoblasts proliferation, indicating that TAp63γ specifically contributes to myoblasts proliferation, independently of p53 and P73. In addition, sh-p63 cells have a defect in mitochondria respiration highlighted by a reduction in spare respiratory capacity and a decrease in complex I, IV protein levels. These results demonstrated that, beside contributing to cell cycle exit, TAp63γ participates to myoblasts metabolism control.

  • p63 and P73, the Ancestors of p53
    Cold Spring Harbor perspectives in biology, 2010
    Co-Authors: Volker Dötsch, D Coutandin, Francesca Bernassola, Eleonora Candi, Gerry Melino
    Abstract:

    P73 and p63 are two homologs of the tumor suppressive transcription factor p53. Given the high degree of structural similarity shared by the p53 family members, P73 and p63 can bind and activate transcription from the majority of the p53-responsive promoters. Besides overlapping functions shared with p53 (i.e., induction of apoptosis in response to cellular stress), the existence of extensive structural variability within the family determines unique roles for p63 and P73. Their crucial and specific functions in controlling development and differentiation are well exemplified by the p63 and P73 knockout mouse phenotypes. Here, we describe the contribution of p63 and P73 to human pathology with emphasis on their roles in tumorigenesis and development.

  • chemotherapy induced apoptosis in hepatocellular carcinoma involves the p53 family and is mediated via the extrinsic and the intrinsic pathway
    International Journal of Cancer, 2010
    Co-Authors: Sarah Seitz, Gerry Melino, Elisa Schulze Schleithoff, W Stremmel, Andreas Koch, Andre Schuster, Andreas Teufel, F Staib, Peter H Krammer
    Abstract:

    We investigated the downstream mechanisms by which chemotherapeutic drugs elicit apoptosis in hepatocellular carcinoma (HCC). Genomic signatures of HCC cell lines treated with different chemotherapeutic drugs were obtained. Analyses of apoptosis pathways were performed and RNA interference was used to evaluate the role of the p53 family. Endogenous p53, p63 and P73 were upregulated in response to DNA damage by chemotherapeutic drugs. Blocking p53 family function led to chemoresistance in HCC. Stimulation and blocking experiments of the CD95-, the TNF- and the TRAIL-receptor systems revealed that cytotoxic drugs, via the p53 family members as transactivators, can trigger expression of each of these death receptors and consequently sensitize HCC cells toward apoptosis. Furthermore, our findings demonstrate a link between chemotherapy, the p53 family and the mitochondrial apoptosis pathway in HCC. Chemotherapeutic treatment induces expression of proapoptotic Bcl-2 family members like Bax and BCL2L11 and the expression of Apaf1, BNIP1, Pdcd8 and RAD. Thus, upon DNA damage, p53, p63 and P73 promote apoptosis via the extrinsic and the intrinsic signaling pathway. In addition, not only proapoptotic genes were upregulated, but also genes known to exert antiapoptotic functions. Bleomycin-induced upregulation of BCL-XL/BCLXL1 and MDM2 suggests that it is the ratio of proapoptotic and antiapoptotic proteins that regulates the apoptosis response of HCC cells toward chemotherapy, thereby playing a decisive role between treatment sensitivity vs. drug resistance. The clinical importance of these data is evidenced by our finding that the bleomycin target gene signature can predict the prognosis of patients suffering from HCC.

  • one two three p53 p63 P73 and chemosensitivity
    Drug Resistance Updates, 2006
    Co-Authors: Martina Muller, Gerry Melino, Elisa Schulze Schleithoff, W Stremmel, Peter H Krammer, Tobias Schilling
    Abstract:

    Molecular links between apoptosis, tumorigenesis and drug resistance provide starting points for new therapeutic approaches and for a targeted cancer therapy. The discovery of the p53-related genes p63 and P73 raised the possibility that they may be cancer-associated genes and as a consequence that p53 is not the only component in predicting prognosis and response to chemotherapy, but instead the status of a network that contains p53, P73 and p63. This review focuses on the status and interrelationship of the p53 family members in human cancer as critical elements for tumor progression and response to therapy. Literature up to December 2006 is reviewed. p63 and P73 – as well as p53 – each use multiple promoters and alternative splicing to generate an array of isoforms, including fulllength isoforms with a transactivation (TA-) domain homologous to that of full-length p53, and amino-terminally truncated (� N-) isoforms.

  • Functional regulation of P73 and p63: development and cancer
    Trends in Biochemical Sciences, 2003
    Co-Authors: Gerry Melino, Xin Lu, Milena Gasco, Tim Crook, Richard A. Knight
    Abstract:

    The transcription factor and tumour suppressor p53 and its two homologues p63 and P73 form a family of proteins. p63 and P73 show much greater molecular complexity than p53 because they are expressed both as multiple alternatively spliced C-terminal isoforms, and as N-terminally deleted, dominant-negative proteins that show reciprocal functional regulation. In addition, several other factors, such as post-translational modifications and specific and common family regulatory proteins, result overall in subtle modulation of their biological effects. Although all p53, p63 and P73 family members are regulators of the cell cycle and apoptosis, the developmental abnormalities of P73- and p63-null mice do not show enhanced tumour susceptibility of p53 knockouts, suggesting that complex regulatory processes modulate the functional effects of this family of proteins.

Frank Mckeon - One of the best experts on this subject based on the ideXlab platform.

  • role of p63 P73 in epithelial remodeling and their response to steroid treatment in nasal polyposis
    The Journal of Allergy and Clinical Immunology, 2011
    Co-Authors: Chun Wei Li, Frank Mckeon, Ke Ke Zhang, Tian Ying Li, Wa Xian, De Yun Wang
    Abstract:

    Background Nasal polyposis (NP) is recognized as aberrant epithelial remodeling, but the molecular mechanism underlying this process is poorly understood. Two important p53 homologues (p63 and P73) play a key role in orchestrating the epithelial development. Objective We intended to study whether p63 and P73 are involved in the epithelial remodeling seen in patients with NP and their response to oral glucocorticosteroid (GC) treatment. Methods Nasal polyp tissues were obtained from 65 patients, and inferior turbinates were obtained from 19 control subjects without NP. Among patients with NP, 20 were treated with oral prednisone, so that 2 sets of polyp biopsy specimens were taken before (GC naive) and after (GC treated) treatment. Immunohistochemistry and quantitative PCR were performed to determine the expression levels of p63 and P73. Results The increase in p63-positive cell numbers was significant in GC-naive NP epithelium (46%) compared with that seen in control epithelium (5%), and it was positively related to the epithelial hyperplasia in patients with NP. The increase in N-terminal transactivation domain P73–positive cell numbers was found in 27% of GC-naive patients with NP and 16% of control subjects, with no statistical difference. The mRNA expression of both p63 and P73 was significantly upregulated in GC-naive patients with NP versus control subjects, and a positive correlation between the p63 and P73 mRNAs was found in all nasal tissues. Furthermore, the improvement of epithelial structure and reduction of p63 mRNA/protein levels were found in patients with NP after GC treatment. Conclusions Our results suggest that the ectopic expression of p63 in multiple cell layers is an important pathologic phenomenon in the epithelial remodeling seen in chronically inflamed airway epithelium (eg, in patients with NP), and its aberrant expression can be suppressed with GC treatment.

  • Genome-Wide Mapping Indicates That P73 and p63 Co-Occupy Target Sites and Have Similar DNA-Binding Profiles In Vivo
    PloS one, 2010
    Co-Authors: Annie Yang, Frank Mckeon, Zhou Zhu, Arminja N. Kettenbach, Philipp Kapranov, Thomas R. Gingeras, Kevin Struhl
    Abstract:

    Background: The p53 homologs, p63 and P73, share, ~85% amino acid identity in their DNA-binding domains, but they have distinct biological functions. Principal Findings: Using chromatin immunoprecipitation and high-resolution tiling arrays covering the human genome, we identify P73 DNA binding sites on a genome-wide level in ME180 human cervical carcinoma cells. Strikingly, the P73 binding profile is indistinguishable from the previously described binding profile for p63 in the same cells. Moreover, the P73:p63 binding ratio is similar at all genomic loci tested, suggesting that there are few, if any, targets that are specific for one of these factors. As assayed by sequential chromatin immunoprecipitation, p63 and P73 co-occupy DNA target sites in vivo, suggesting that p63 and P73 bind primarily as heterotetrameric complexes in ME180 cells. Conclusions: The observation that p63 and P73 associate with the same genomic targets suggest that their distinct biological functions are due to cell-type specific expression and/or protein domains that involve functions other than DNA binding. © 2010 Yang et al.

  • tumor predisposition in mice mutant for p63 and P73 evidence for broader tumor suppressor functions for the p53 family
    Cancer Cell, 2005
    Co-Authors: Elsa R Flores, Denise Crowley, Shomit Sengupta, Annie Yang, John B Miller, Jamie J Newman, Roderick T Bronson, Frank Mckeon
    Abstract:

    Summary p63 and P73 are functionally and structurally related to the tumor suppressor p53 . However, their own role in tumor suppression is unclear. Given the p53 -like properties of p63 and P73 , we tested whether they are involved in tumor suppression by aging mice heterozygous for mutations in all p53 family genes and scored for spontaneous tumors. We show here that p63 +/− ; P73 +/− mice develop spontaneous tumors. Loss of p63 and P73 can also cooperate with loss of p53 in tumor development. Mice heterozygous for mutations in both p53 and p63 or p53 and P73 displayed higher tumor burden and metastasis compared to p53 +/− mice. These findings provide evidence for a broader role for the p53 family than has been previously reported.

  • p63 and P73 are not required for the development and p53 dependent apoptosis of t cells
    Cancer Cell, 2004
    Co-Authors: Makoto Senoo, John P Manis, Frederick W Alt, Frank Mckeon
    Abstract:

    The recent discoveries of p63 and P73, homologs of the tumor suppressor p53, raised the possibility of a network of these family members governing cell cycle arrest and apoptosis in response to stress. However, mice lacking P73 show no tendency for spontaneous tumors, and mutations in p63 or P73 are rare in human tumors, rendering any obligate role of these genes in cell death and tumor suppression unclear. In an effort to reconcile these incongruent data, we examined the genetic interactions between p53, p63, and P73 in well-established paradigms of p53-dependent and -independent T cell death using primary, genetically defined lymphocytes. Our findings challenge the generality of the notion that p63 and P73 are required for p53 function or for apoptosis in T cells.

  • loss of p63 expression is associated with tumor progression in bladder cancer
    American Journal of Pathology, 2002
    Co-Authors: Marshall J Urist, Frank Mckeon, Charles J Di Como, Elizabeth Charytonowicz, David Verbel, Christopher P Crum, Tan A Ince, Carlos Cordoncardo
    Abstract:

    p63, a member of the p53 gene family, encodes multiple proteins that may either transactivate p53 responsive genes (TAp63) or act as a dominant-negative factor toward p53 and P73 (ΔNp63). p63 is expressed in many epithelial compartments and p63−/− mice fail to develop skin, prostate, and mammary glands among other defects. It has been previously shown that p63 is expressed in normal urothelium. This study reports that p63 is regulated in bladder carcinogenesis and that p63 expression is lost in most invasive cancers whereas papillary superficial tumors maintain p63 expression. Examination of bladder carcinoma cell lines reveals that certain lines derived from invasive carcinomas maintain expression of ΔNp63, as demonstrated by both immunoblotting and confirmed by isoform-specific quantitative reverse transcriptase-polymerase chain reaction. Another novel finding reported in this study is the fact that p63−/− mice develop a bladder mucosa epithelial layer yet fail to complete uroepithelial differentiation, producing a nontransitional default cuboidal epithelium. These data indicate that in contrast to the skin and prostate, p63 is not required for formation of a bladder epithelium but is indispensable for the specific differentiation of a transitional urothelium.

Annie Yang - One of the best experts on this subject based on the ideXlab platform.

  • Genome-Wide Mapping Indicates That P73 and p63 Co-Occupy Target Sites and Have Similar DNA-Binding Profiles In Vivo
    PloS one, 2010
    Co-Authors: Annie Yang, Frank Mckeon, Zhou Zhu, Arminja N. Kettenbach, Philipp Kapranov, Thomas R. Gingeras, Kevin Struhl
    Abstract:

    Background: The p53 homologs, p63 and P73, share, ~85% amino acid identity in their DNA-binding domains, but they have distinct biological functions. Principal Findings: Using chromatin immunoprecipitation and high-resolution tiling arrays covering the human genome, we identify P73 DNA binding sites on a genome-wide level in ME180 human cervical carcinoma cells. Strikingly, the P73 binding profile is indistinguishable from the previously described binding profile for p63 in the same cells. Moreover, the P73:p63 binding ratio is similar at all genomic loci tested, suggesting that there are few, if any, targets that are specific for one of these factors. As assayed by sequential chromatin immunoprecipitation, p63 and P73 co-occupy DNA target sites in vivo, suggesting that p63 and P73 bind primarily as heterotetrameric complexes in ME180 cells. Conclusions: The observation that p63 and P73 associate with the same genomic targets suggest that their distinct biological functions are due to cell-type specific expression and/or protein domains that involve functions other than DNA binding. © 2010 Yang et al.

  • tumor predisposition in mice mutant for p63 and P73 evidence for broader tumor suppressor functions for the p53 family
    Cancer Cell, 2005
    Co-Authors: Elsa R Flores, Denise Crowley, Shomit Sengupta, Annie Yang, John B Miller, Jamie J Newman, Roderick T Bronson, Frank Mckeon
    Abstract:

    Summary p63 and P73 are functionally and structurally related to the tumor suppressor p53 . However, their own role in tumor suppression is unclear. Given the p53 -like properties of p63 and P73 , we tested whether they are involved in tumor suppression by aging mice heterozygous for mutations in all p53 family genes and scored for spontaneous tumors. We show here that p63 +/− ; P73 +/− mice develop spontaneous tumors. Loss of p63 and P73 can also cooperate with loss of p53 in tumor development. Mice heterozygous for mutations in both p53 and p63 or p53 and P73 displayed higher tumor burden and metastasis compared to p53 +/− mice. These findings provide evidence for a broader role for the p53 family than has been previously reported.

  • p63 and P73 are required for p53 dependent apoptosis in response to dna damage
    Nature, 2002
    Co-Authors: Elsa R Flores, Kenneth Y Tsai, Denise Crowley, Shomit Sengupta, Annie Yang, Frank Mckeon, Tyler Jacks
    Abstract:

    The tumour-suppressor gene p53 is frequently mutated in human cancers and is important in the cellular response to DNA damage1,2. Although the p53 family members p63 and P73 are structurally related to p53, they have not been directly linked to tumour suppression, although they have been implicated in apoptosis3,4,5,6,7,8,9. Given the similarity between this family of genes and the ability of p63 and P73 to transactivate p53 target genes10,11, we explore here their role in DNA damage-induced apoptosis. Mouse embryo fibroblasts deficient for one or a combination of p53 family members were sensitized to undergo apoptosis through the expression of the adenovirus E1A oncogene12,13,14. While using the E1A system facilitated our ability to perform biochemical analyses, we also examined the functions of p63 and P73 using an in vivo system in which apoptosis has been shown to be dependent on p53. Using both systems, we show here that the combined loss of p63 and P73 results in the failure of cells containing functional p53 to undergo apoptosis in response to DNA damage.

  • on the shoulders of giants p63 P73 and the rise of p53
    Trends in Genetics, 2002
    Co-Authors: Annie Yang, Mourad Kaghad, Daniel Caput, Frank Mckeon
    Abstract:

    The discoveries of the p53 homologs, p63 and P73, have both fueled new insights and exposed enigmas in our understanding of the iconic p53 tumor suppressor. Although the pivotal role of p53 in cancer pathways remains unchallenged, because p63 and P73 are now implicated in stem cell identity, neurogenesis, natural immunity and homeostatic control. Despite their seemingly separate tasks, there are hints that the p53 family members both collaborate and interfere with one another. The question remains, therefore, as to whether these genes evolved to function independently or whether their familial ties still bind them in pathways of cell proliferation, death and tumorigenesis.

  • p63 and P73 p53 mimics menaces and more
    Nature Reviews Molecular Cell Biology, 2000
    Co-Authors: Annie Yang, Frank Mckeon
    Abstract:

    Inactivation of the tumour suppressor p53 is the most common defect in cancer cells. The discovery of its two close relatives, p63 and P73, was therefore both provocative and confounding. Were these new genes tumour suppressors, p53 regulators, or evolutionary spin-offs? Both oncogenic and tumour-suppressor properties have now been attributed to the p53 homologues, perhaps reflecting the complex, often contradictory, protein products encoded by these genes. p63 and P73 are further implicated in many p53-independent pathways, including stem-cell regeneration, neurogenesis and sensory processes.

Leif W Ellisen - One of the best experts on this subject based on the ideXlab platform.

  • a microrna dependent circuit controlling p63 P73 homeostasis p53 family cross talk meets therapeutic opportunity
    Oncotarget, 2011
    Co-Authors: Benjamin Ory, Leif W Ellisen
    Abstract:

    Benjamin Ory and Leif W. Ellisen * Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA 02114, USA Received: March 9, 2011; Accepted: March 23, 2011; Published: March 23, 2011; Keywords: p63, P73, microRNA, apoptosis, cisplatin, squamous cell carcinoma, triple-negative breast cancer, chemosensitivity Correspondence: Leif W. Ellisen, e-mail: // // Abstract The p53 family transcription factors p53, p63 and P73 make diverse contributions in development and cancer. Mutation or deletion of p53 is observed in the majority of human cancers. In contrast, p63 and P73 are not lost in cancer but mediate distinct genetic roles in normal and tumor-specific contexts: P73 promotes genome stability and mediates chemosensitivity, while p63 largely lacks these p53-like functions and instead promotes proliferation and cell survival. We recently uncovered a mechanism which maintains p63/P73 homeostasis within the epithelium through direct transcriptional regulation of microRNAs (miRs). We discovered that several of the top p63-regulated miRs target P73 for inhibition, including miR-193a-5p, a direct p63/P73 transcriptional target which is repressed by p63 and activated by P73 both in vitro and in vivo . The resulting feed-forward circuit involving p63, miR-193a-5p and P73 controls P73 levels, cell viability and DNA damage susceptibility in certain cancers including squamous cell carcinoma. Here, we discuss the evolutionary implications of this regulatory circuit, which may point to a general mechanism of miR-mediated cross-talk within transcription factor gene families. Additionally, we suggest that inducible chemoresistance mediated by this miR-dependent mechanism might be an attractive target for therapeutic intervention.

  • a microrna dependent program controls p53 independent survival and chemosensitivity in human and murine squamous cell carcinoma
    Journal of Clinical Investigation, 2011
    Co-Authors: Benjamin Ory, Matthew R Ramsey, Catherine Wilson, Douangsone D Vadysirisack, Nicole Forster, James W Rocco, Michael S Rothenberg, Leif W Ellisen
    Abstract:

    The p53 tumor suppressor, a central mediator of chemosensitivity in normal cells, is functionally inactivated in many human cancers. Therefore, a central challenge in human cancer therapy is the identification of pathways that control tumor cell survival and chemosensitivity in the absence of functional p53. The p53-related transcription factors p63 and P73 exhibit distinct functions — P73 mediates chemosensitivity while p63 promotes proliferation and cell survival — and are both overexpressed in squamous cell carcinomas (SCCs). However, how p63 and P73 interact functionally and govern the balance between prosurvival and proapoptotic programs in SCC remains elusive. Here, we identify a microRNA-dependent mechanism of p63/P73 crosstalk that regulates p53-independent survival of both human and murine SCC. We first discovered that a subset of p63-regulated microRNAs target P73 for inhibition. One of these, miR-193a-5p, expression of which was repressed by p63, was activated by proapoptotic P73 isoforms in both normal cells and tumor cells in vivo. Chemotherapy caused p63/P73-dependent induction of this microRNA, thereby limiting chemosensitivity due to microRNA-mediated feedback inhibition of P73. Importantly, inhibiting miR-193a interrupted this feedback and thereby suppressed tumor cell viability and induced dramatic chemosensitivity both in vitro and in vivo. Thus, we have identified a direct, microRNA-dependent regulatory circuit mediating inducible chemoresistance, whose inhibition may provide a new therapeutic opportunity in p53-deficient tumors.

  • tumor specific P73 up regulation mediates p63 dependence in squamous cell carcinoma
    Cancer Research, 2006
    Co-Authors: Maurice Phillip Deyoung, James W Rocco, Cheeonn Leong, Cory M Johannessen, William C Faquin, Leif W Ellisen
    Abstract:

    p63 is essential for normal epithelial development and is overexpressed in the vast majority of squamous cell carcinomas (SCC). Recent work had shown that ΔNp63α is essential for survival of SCC cells, raising the possibility that the p63 pathway may be an attractive therapeutic target in these tumors. Nevertheless, it is unknown whether a therapeutic window exists for inhibiting p63 in tumor cells versus normal epithelia. Here, we show that SCC cells are uniquely dependent on ΔNp63α for survival, unlike normal p63-expressing epithelial cells, and that dependence is mediated through tumor-specific up-regulation of the related protein P73. In normal primary human keratinocytes, we find that inhibition of endogenous p63 by RNA interference (RNAi) induces p21CIP1 expression, inhibits cell cycle progression, and ultimately promotes cellular senescence. In contrast, p63 inhibition in SCC cells induces proapoptotic bcl-2 family members and rapidly triggers apoptosis. Expression of P73 is low in uncultured basal keratinocytes but is markedly up-regulated in both SCC cell lines and primary tumors in vivo. Whereas p21CIP1 induction following loss of p63 in normal cells is independent of p53 and P73, both proapoptotic gene induction and cell death following p63 RNAi in tumor cells are P73 dependent. Finally, ectopic P73 expression in primary keratinocytes does not affect baseline cell proliferation but is sufficient to trigger cell death following loss of p63. Together, these findings define a specific molecular mechanism of p63 dependence through P73 up-regulation, and they provide a rationale for targeting the p63 pathway as a therapeutic strategy in SCCs. (Cancer Res 2006; 66(19): 9362-8)

  • p63 mediates survival in squamous cell carcinoma by suppression of P73 dependent apoptosis
    Cancer Cell, 2006
    Co-Authors: James W Rocco, Cheeonn Leong, Nicolas Kuperwasser, Maurice Phillip Deyoung, Leif W Ellisen
    Abstract:

    We demonstrate that deltaNp63alpha is an essential survival factor in head and neck squamous cell carcinoma (HNSCC) through its ability to suppress P73-dependent apoptosis. Inhibition of endogenous p63 expression by RNAi induces apoptosis selectively in HNSCC cells that overexpress deltaNp63alpha. Knockdown of p63 induces the proapoptotic bcl-2 family members Puma and Noxa, and both their induction and subsequent cell death are p53 independent but require transactivating isoforms of P73. Inhibition of P73-dependent transcription by deltaNp63alpha involves both direct promoter binding and physical interaction with P73. In HNSCC cells lacking endogenous deltaNp63alpha expression, bcl-2 is instead upregulated and can suppress P73-mediated death. Together, these data define a pathway whereby deltaNp63alpha promotes survival in squamous epithelial malignancy by repressing a P73-dependent proapoptotic transcriptional program.

Elsa R Flores - One of the best experts on this subject based on the ideXlab platform.

  • p53 p63 P73 in the epidermis in health and disease
    Cold Spring Harbor Perspectives in Medicine, 2014
    Co-Authors: Vladimir A Botchkarev, Elsa R Flores
    Abstract:

    The p53 gene family is derived from a common ancestor that appeared very early during evolution in the metazoan sea anemone more than a billion years ago (Belyi et al. 2010). This ancestor gene duplicated in early vertebrates resulting in the appearance of the gene that is closely related to p53, whereas its second duplication in bony fish led to the appearance of the p63 and P73 genes (Belyi et al. 2010). During evolution, the p63 and P73 genes showed a marked increase in the number of introns resulting in the appearance of their numerous isoforms in vertebrates. In contrast, the structure of the p53 gene did not change dramatically (Belyi et al. 2010). The expansion of the p53 gene family in vertebrates, whose role was originally linked to the protection of germ cells against DNA damage in early metazoans, resulted in a diversity of novel functions including the control of cell proliferation, differentiation, tissue development, stem cell regulation, and tumor suppression (Flores et al. 2005; Belyi et al. 2010; Allocati et al. 2012). During the last two decades, tremendous progress has been achieved in the delineation of the functions of the p53 family of genes in mammals (Lane and Levine 2010). In particular, the structure and role for the p63 gene as a master regulator of the development and maintenance of the stratified epithelia as well as its involvement in the control of aging and tumor growth were shown (reviewed in Koster and Roop 2007; Crum and McKeon 2010; Melino 2011; Vanbokhoven et al. 2011; Su et al. 2013). Furthermore, the roles of the distinct p63 and P73 isoforms in the control of cell proliferation, differentiation, and apoptosis in the skin were dissected by using a number of genetically engineered mouse models and in vitro analyses. Consistent with the role of p53 in genome surveillance, p53 mutations are found in more than half of human tumors including squamous cell carcinomas, and missense p53 mutations lead to aggressive cancer phenotypes (Muller and Vousden 2013). In contrast to p53, mutations of the p63 gene cause numerous ectodermal dysplasia syndromes also associated with craniofacial and limb abnormalities (for review, see Rinne et al. 2007; Vanbokhoven et al. 2011). Unlike p53 and p63, mutations in the P73 gene are extremely rare; however, P73 is inactivated in cancers epigenetically, that is, via hypermethylation of its promoter (Maas et al. 2013). In this review, we summarize our current knowledge of the role of the p53 gene family in the control of skin development, regeneration, tumorigenesis, and response to chemotherapy. We also discuss the distinct roles for different p63 and P73 isoforms in the regulation of skin regeneration and tumor growth. Finally, we discuss directions for further research in these exciting areas of skin biology and pathology.

  • p63 and P73 transcriptionally regulate genes involved in dna repair
    PLOS Genetics, 2009
    Co-Authors: Yu Li Lin, Shomit Sengupta, Tyler Jacks, Katherine Gurdziel, George W Bell, Elsa R Flores
    Abstract:

    The p53 family activates many of the same genes in response to DNA damage. Because p63 and P73 have structural differences from p53 and play distinct biological functions in development and metastasis, it is likely that they activate a unique transcriptional network. Therefore, we performed a genome-wide analysis using cells lacking the p53 family members after treatment with DNA damage. We identified over 100 genes involved in multiple pathways that were uniquely regulated by p63 or P73, and not p53. Further validation indicated that BRCA2, Rad51, and mre11 are direct transcriptional targets of p63 and P73. Additionally, cells deficient for p63 and P73 are impaired in DNA repair and p63+/−;P73+/− mice develop mammary tumors suggesting a novel mechanism whereby p63 and P73 suppress tumorigenesis.

  • tumor predisposition in mice mutant for p63 and P73 evidence for broader tumor suppressor functions for the p53 family
    Cancer Cell, 2005
    Co-Authors: Elsa R Flores, Denise Crowley, Shomit Sengupta, Annie Yang, John B Miller, Jamie J Newman, Roderick T Bronson, Frank Mckeon
    Abstract:

    Summary p63 and P73 are functionally and structurally related to the tumor suppressor p53 . However, their own role in tumor suppression is unclear. Given the p53 -like properties of p63 and P73 , we tested whether they are involved in tumor suppression by aging mice heterozygous for mutations in all p53 family genes and scored for spontaneous tumors. We show here that p63 +/− ; P73 +/− mice develop spontaneous tumors. Loss of p63 and P73 can also cooperate with loss of p53 in tumor development. Mice heterozygous for mutations in both p53 and p63 or p53 and P73 displayed higher tumor burden and metastasis compared to p53 +/− mice. These findings provide evidence for a broader role for the p53 family than has been previously reported.

  • p63 and P73 are required for p53 dependent apoptosis in response to dna damage
    Nature, 2002
    Co-Authors: Elsa R Flores, Kenneth Y Tsai, Denise Crowley, Shomit Sengupta, Annie Yang, Frank Mckeon, Tyler Jacks
    Abstract:

    The tumour-suppressor gene p53 is frequently mutated in human cancers and is important in the cellular response to DNA damage1,2. Although the p53 family members p63 and P73 are structurally related to p53, they have not been directly linked to tumour suppression, although they have been implicated in apoptosis3,4,5,6,7,8,9. Given the similarity between this family of genes and the ability of p63 and P73 to transactivate p53 target genes10,11, we explore here their role in DNA damage-induced apoptosis. Mouse embryo fibroblasts deficient for one or a combination of p53 family members were sensitized to undergo apoptosis through the expression of the adenovirus E1A oncogene12,13,14. While using the E1A system facilitated our ability to perform biochemical analyses, we also examined the functions of p63 and P73 using an in vivo system in which apoptosis has been shown to be dependent on p53. Using both systems, we show here that the combined loss of p63 and P73 results in the failure of cells containing functional p53 to undergo apoptosis in response to DNA damage.